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Ketone bodies
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Ketone bodies
Ketone bodies are three water-soluble compounds that are produced as by-products
when fatty acids are broken down for energy in the liver and kidney. Two of the
three are used as a source of energy in the heart and brain while the third is a waste
product excreted from the body. In the brain, they are a vital source of energy during
fasting.[1] Although termed "bodies", they are dissolved substances, not particles.
The three endogenous ketone bodies are acetone, acetoacetic acid, and
beta-hydroxybutyric acid,[2] although beta-hydroxybutyric acid is not technically a
ketone but a carboxylic acid. Other ketone bodies such as beta-ketopentanoate and
beta-hydroxypentanoate may be created as a result of the metabolism of synthetic
triglycerides such as triheptanoin.
Uses in the heart and brain
Ketone bodies can be used for energy. Ketone bodies are transported from the liver
to other tissues, where acetoacetate and beta-hydroxybutyrate can be reconverted to
acetyl-CoA to produce energy, via the citric acid cycle.
The heart gets little energy from ketone bodies except under special circumstances;
it uses mainly fatty acids.[3]
Chemical structures of the three
ketone bodies: acetone (top),
acetoacetic acid (middle), and
beta-hydroxybutyric acid
(bottom).
The brain gets a portion of its energy from ketone bodies when glucose is less
available (e.g., during fasting, strenuous exercise, low carbohydrate, ketogenic diet and in neonates). In the event of
low blood glucose, most other tissues have additional energy sources besides ketone bodies (such as fatty acids), but
the brain does not. After the diet has been changed to lower blood glucose for 3 days, the brain gets 25% of its
energy from ketone bodies.[4] After about 4 days, this goes up to 70% (during the initial stages the brain does not
burn ketones, since they are an important substrate for lipid synthesis in the brain).
Production
Ketone bodies are produced from acetyl-CoA (see ketogenesis) mainly
in the mitochondrial matrix of hepatocytes when carbohydrates are so
scarce that energy must be obtained from breaking down fatty acids.
Because of the high level of acetyl CoA present in the cell, the
pyruvate dehydrogenase complex is inhibited, whereas pyruvate
carboxylase becomes activated. The oxaloacetate produced will enter
Acetyl-CoA
gluconeogenesis rather than the citric acid cycle, and the latter is also
inhibited by the elevated level of NADH resulting from ß-oxidation of fatty acids. Unable to be used in the citric acid
cycle, the excess acetyl-CoA is therefore rerouted to ketogenesis. Such a state in humans is referred to as the fasted
state.
Acetone is produced by spontaneous decarboxylation of acetoacetate (meaning this ketone body will break down in
five hours if it is not needed for energy and be removed as waste. This "use it or lose it" factor contributes to much of
the weight loss found in ketogenic diets.). Acetone cannot be converted back to acetyl-CoA, so it is excreted in the
urine, or (as a consequence of its high vapor pressure) exhaled. Acetone is responsible for the characteristic "fruity"
odor of the breath of persons in ketoacidosis.[5]
Ketone bodies
Ketosis and ketoacidosis
Any production of these compounds is called ketogenesis, and this is necessary in small amounts.
However, when excess ketone bodies accumulate, this abnormal state is called ketosis. Ketosis can be quantified by
sampling the patient's exhaled air, and testing for acetone by gas chromatography.[6] Many diabetics self test for the
presence of ketones using blood or urine testing kits.
When even larger amounts of ketone bodies accumulate such that the blood's pH is lowered to dangerously acidic
levels, this state is called ketoacidosis.
Impact upon pH
Both acetoacetic acid and beta-hydroxybutyric acid are acidic, and, if levels of these ketone bodies are too high, the
pH of the blood drops, resulting in ketoacidosis.
This happens most often in untreated Type I diabetes, and somewhat less often in Type II (see diabetic ketoacidosis).
References
[1] Mary K. Campbell, Shawn O. Farrell (2006). Biochemistry (5th ed.). Cengage Learning. p. 579. ISBN 0534405215.
[2] Lori Laffel (1999). "Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes".
Diabetes/Metabolism Research and Reviews 15 (6): 412–426.
doi:10.1002/(SICI)1520-7560(199911/12)15:6<412::AID-DMRR72>3.0.CO;2-8. PMID 10634967.
[3] Kodde IF, van der Stok J, Smolenski RT, de Jong JW (January 2007). "Metabolic and genetic regulation of cardiac energy substrate
preference". Comp. Biochem. Physiol., Part a Mol. Integr. Physiol. 146 (1): 26–39. doi:10.1016/j.cbpa.2006.09.014. PMID 17081788.
[4] Hasselbalch, SG; Knudsen, GM; Jakobsen, J; Hageman, LP; Holm, S; Paulson, OB (1994). "Brain metabolism during short-term starvation in
humans.". Journal of cerebral blood flow and metabolism 14 (1): 125–31. doi:10.1038/jcbfm.1994.17. PMID 8263048.
[5] American Diabetes Association-Ketoacidosis (http:/ / www. diabetes. org/ living-with-diabetes/ complications/ ketoacidosis-dka. html)
[6] K. Musa-Veloso, S. S. Likhodii and S. C. Cunnane (2002). "Breath acetone is a reliable indicator of ketosis in adults consuming ketogenic
meals" (http:/ / www. ajcn. org/ cgi/ content/ abstract/ 76/ 1/ 65). Am J Clin Nutr 76 (1): 65–70. PMID 12081817. .
External links
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emerg/135 (http://www.emedicine.com/emerg/topic135.htm#) at eMedicine - Diabetic Ketoacidosis
Fat metabolism at unisanet.unisa.edu.au (http://www.unisanet.unisa.edu.au/08366/h&p2fat.htm)
NHS Direct Online Health Encyclopaedia, Ketosis (http://www.nhsdirect.nhs.uk/en.asp?TopicID=274)
BioCarta Pathways Formation of Ketone Bodies (http://www.biocarta.com/pathfiles/ketonebodiesPathway.
asp)
• MeSH Ketone+Bodies (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Ketone+Bodies)
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